Proteolytic enzymes represented by CANP and including, e.g., cathepsin B, papain, ficin, bromelin, and bromelan are generally called thiol proteases because they have a thiol group at the active center. On the other hand, it is known that substances having CANP inhibition activity not only specifically affect the thiol group of the CANP to inhibit its activity but also have an inhibitory effect on other thiol proteases.
Therefore, substances capable of inhibiting proteases such as CANP and cathepsin B are expected to useful the cure, mitigation, treatment, or prevention of diseases to which these proteases are related, e.g., myotonic dystrophy, inflammation, renal hypertension, cataract, myocardial infarct, viral infectious diseases, malignant tumors, osteoporosis, and allergic diseases.
Conventionally known examples of a compound having thiol protease inhibition activity are E-64, a mold metabolite, a series of epoxy succinic acid derivatives such as E-64-c as derivatives of E-64, and aldehyde derivatives of leupeptin and antipine belonging to a secondary metabolite of an actinomycete.
E-64 is an epoxysuccinic acid derivative obtained from a bran solid culture of an Aspergillus japonicus TPR-64 strain and represented by the following formula (e.g., Published Unexamined Japanese Patent Application No. 52-23021 and Published Examined Japanese Patent Application No. 64-5031): ##STR2##
Both E-64-c and loxistatin as its ethylester are derivatives of the above E-64 and are represented by the following formula (e.g., Published Unexamined Japanese Patent Application No. 55-115878): ##STR3##
The above two compounds, especially loxistatin, have attracted attention due to their effect as proteolytic enzyme inhibitors, and are therefore currently being studied to develop a practical use therefor an agent for treating muscular dystrophy and the like.